The present invention concerns the heterocyclic carbon compounds of the 1,4-dihydropyridine class with a 3-carboxylate group linked to an alkyleneaminoalkyleneheteroatom group moiety. These compounds possess bio-affecting properties.
A substantial body of prior art has evolved over the last decade involving compounds of 4-aryl-1,4-dihydropyridine series which have calcium antagonist properties and are useful in the treatment of cardiovascular diseases. These calcium blocking effects appear to mediate vasodilation making these compounds useful in treating angina and hypertension. The archetypical compound of this series is nifedipine (formula 1): ##STR3## chemically, 4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine. Nifedipine and some related 4-aryl-1,4-dihydropyridines are the subject of U.S. Pat. No. 3,485,847 issued Dec. 23, 1969. Numerous subsequent patents have been granted covering 1,4-dihydropyridines in which other substituent groups have been incorporated at the various ring positions of the dihydropyridine moiety via a diversity of chemical bonding groups. Many of the numerous reference patent documents directed to this class of compounds are distinguished by relatively minor structural changes in one or both of the carboxylate groups of the dihydropyridine nucleus.
U.S. Pat. No. 3,985,785 discloses the useful cardiovascular agent, Nicardipine (2), and related compounds. ##STR4##
Other series of compounds related to Nicardipine may be generalized by the following structural formula (3) ##STR5## wherein R.sup.2, R.sup.4, R.sup.5 and R.sup.6 could be any of a number of substituent groups which have been repeatedly defined previously in the voluminous dihydropyridine literature; but with specific attention given to defining the substituent structure attached to the 3-position of the 1,4-dihydropyridine ring. The 3-position structural fragment comprises a secondary or tertiary amino function linked by means of an alkylene chain to the carboxylate group. The alkylene group, varying from 2 to 6 carbon atoms, can be straight chain or branched. In some instances, an aryl or hetaryl group is attached to the alkylene chain. For the two amino nitrogen substituents, R.sup.7 is hydrogen or alkyl and R.sup.8 can be alkyl, aralkyl, or aryl. The following references are representative of the art directed to Nicardipine-type compounds with a C-3 structural fragment of formula (4). ##STR6##
Araki, et al., U.S. Pat. No. 4,423,052 disclose compounds wherein m is 0, n is 1 or 2, R.sup.7 and R.sup.8 are alkyl or arylalkyl, R.sup.9 is hydrogen and is aryl.
Similar compounds were disclosed in Chem. Abstracts, 98, 107166j (1983) wherein m is 0 to 3, n is 0 or 1, R.sup.7 and R.sup.8 are alkyl or aralkyl, R.sup.9 is hydrogen and R.sup.10 is aryl.
Compounds are disclosed in European patent application No. 128,010 in which m and n can be 0 to 6, R.sup.7 and R.sup.9 are alkyl, R.sup.8 is optimally substituted aralkyl, and R.sup.10 is hydrogen or alkyl.
In Japanese patent document No. J5 8,157,785A (abstract No. 83-798692/43) compounds were disclosed wherein m equals 0, n equals 1 or 2, R.sup.7 and R.sup.8 are alkyl, R.sup.9 is hydrogen, and R.sup.10 is a heterocyclic group.
Finally, patent applications have been published, e.g. DE No. 3522-579-A (abstract No. 86-008339/02); assigned to Toyama Chem. KK which disclose compounds where R.sup.7 is ##STR7## with Y being O, S or vinylene, W being O, S or alkylene, and Q being a nitrogen-containing heterocycle.
Of less relevance to the compounds of the instant invention would be those compounds which can be generalized by formula (5). ##STR8## Compounds in this class are distinguished by the side-chain amino nitrogen atom being incorporated into a ring, generally of 5 to 7 members. In some instances, the ring may contain another heteroatom such as a nitrogen, e.g. a piperazine ring. Representative references for this type of dihydropyridine analog structure (5) would be the following:
European patent application No. 88,903-A (Yoshitomi Pharm. KK).
European patent application No. 94,159-A (Takeda Chem. Ind. Ltd.).
European patent application No. 97,821 (Pierrel SPA).
The compounds of the instant invention are distinguished over the art as they contain an additional aryl or hetaryl moiety, connected by a heteroatom and short alkylene chain to the amino nitrogen atom of the 3-carboxylate side chain. This particular structural elaboration, which is neither suggested nor made obvious by prior art, results in compounds which possess pharmacologic properties that would make them useful as cardiovascular agents. In essence, the instant compounds may be distinguished over compounds of the prior art both on the basis of molecular structure but also by biological action. While the instant compounds possess calcium channel blocking properties, as do the prior art compounds, the instant compounds have also been found to possess useful actions in protecting against ischemia and in inhibiting the aggregation of blood platelets. In summary, there is nothing in the prior art which anticipates or suggests the compounds of the instant invention.